Agarwal S_ British Journal of Clinical Pharmacology

Title
Effect of Ketoconazole, a Strong CYP3A Inhibitor, on the Pharmacokinetics of
Venetoclax, a BCL-2 Inhibitor, in Patients with Non-Hodgkin Lymphoma

Running head: Venetoclax and ketoconazole drug interaction in non-Hodgkin

lymphoma

Authors

Suresh K. Agarwal1; Ahmed Hamed Salem1,2; Alexey V. Danilov3,4; Beibei Hu1; Soham
Puvvada5; Martin Gutierrez6, David Chien7; Lionel D. Lewis3; Shekman L. Wong1

1
Clinical Pharmacology and Pharmacometrics, AbbVie Inc., North Chicago, IL, USA
2
Department of Clinical Pharmacy, Faculty of Pharmacy, Ain Shams University, Cairo,
Egypt
3
Department of Medicine, The Geisel School of Medicine at Dartmouth and The Norris
Cotton Cancer Center at the Dartmouth-Hitchcock Medical Center, Lebanon, NH, USA
4
Current address: Knight Cancer Institute, Oregon Health and Science University,
Portland, OR, USA
5
The University of Arizona Cancer Center, Tucson, AZ, USA
6
The Cancer Center at Hackensack University Medical Center, Hackensack, NJ, USA
7
Oncology Development, AbbVie Inc., North Chicago, IL, USA

Correspondence: Ahmed Hamed Salem

AbbVie Inc. Dept. R4PK, Bldg. AP31-3
1 North Waukegan Road
North Chicago, IL 60064
Telephone: +1 (847) 938-0776

This article has been accepted for publication and undergone full peer review but has not
been through the copyediting, typesetting, pagination and proofreading process which may
lead to differences between this version and the Version of Record. Please cite this article as
doi: 10.1111/bcp.13175

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Facsimile: +1 (847) 938-5193
Email: [email protected]

The principal investigator for this study is Dr. Lionel D. Lewis, The Geisel School of
Medicine at Dartmouth and The Norris Cotton Cancer Center at the Dartmouth-Hitchcock
Medical Center, Lebanon, NH, USA.

Key words: venetoclax, ketoconazole, drug-drug interaction, pharmacokinetics, BCL-2

Word count: 3,005; 4 Figures and 3 Tables

Summary

Aim: To examine the effect of a strong CYP3A inhibitor, ketoconazole, on the

pharmacokinetics, safety, and tolerability of venetoclax.

Methods: Twelve patients with Non-Hodgkin lymphoma (NHL) were enrolled in this

Phase 1, open-label, fixed-sequence study. Patients received a single 50 mg dose of

venetoclax orally on Day 1 and Day 8, and a 400 mg once daily dose of ketoconazole on

Days 5 through 11. Blood samples were collected predose and up to 96 hours after each

venetoclax dose on Day 1 and Day 8.

Results: Eleven patients had evaluable pharmacokinetic data and were, therefore,

included in the statistical analyses. Compared to administration of a single 50 mg dose of

venetoclax alone, ketoconazole increased the venetoclax mean maximum observed

plasma concentration (Cmax) and area under the plasma concentration-time curve from

time 0 to infinity (AUC∞) by 2.3-fold (90% confidence interval [CI]: 2.0–2.7) and

6.4-fold (90% CI: 4.5–9.2; range: 2- to 12-fold), respectively.

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Conclusions: Coadministration of venetoclax with multiple doses of ketoconazole

resulted in a significant increase of venetoclax exposures strongly suggesting that CYP3A

plays a major role in elimination of venetoclax in patients. These results suggest the need

to avoid concomitant use with strong and moderate inhibitors or inducers of CYP3A

during the venetoclax ramp-up phase in chronic lymphocytic leukemia (CLL) patients.

For patients who have completed the ramp-up phase, a modification in venetoclax dose

for use with strong inhibitors or inducers of CYP3A/P-gp is recommended.

What is Already Known about this Subject

 Venetoclax has demonstrated clinical efficacy and safety in a variety of

hematological malignancies.

 In vitro, venetoclax and its major metabolite (M27) are metabolized primarily by

cytochrome P450 (CYP) 3A

What this Study Adds

 Ketoconazole increased venetoclax mean Cmax and AUC∞ by 2.3- and 6.4-fold,

respectively, compared to administration of venetoclax alone. These results

indicate that CYP3A plays a major role in elimination of venetoclax in patients.

 These results suggest the need for avoiding concomitant use of venetoclax with

strong and moderate CYP3A inhibitors in CLL patients during the venetoclax

ramp-up phase.

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 Tables of Links
LIGANDS
ketoconazole
midazolam
navitoclax
venetoclax

TARGETS
Other protein targetsa
BCL-2 Family
BCL-XL
BCL-2
Transportersb
P-gp
BCRP
Enzymesc
CYP3A4

These Tables of Links list key protein targets and ligands in this article that are

hyperlinked* to corresponding entries in http://www.guidetopharmacology.org, the

common portal for data from the IUPHAR/BPS Guide to PHARMACOLOGY (Southan

et al., 2016), and are permanently archived in The Concise Guide to PHARMACOLOGY

2015/16 (a,b,cAlexander et al., 2015a,b,c).

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Introduction

Venetoclax (ABT-199, GDC-0199) is a selective, potent, first-in-class, BCL-2 family

protein inhibitor in the biarylacylsulfonamide chemical class that restores programmed

cell death (apoptosis) in cancer cells. Antiapoptotic BCL-2 family members are

associated with tumor initiation, disease progression, and chemotherapy resistance.

Overexpression of BCL-2 family members is a major contributor to the pathogenesis of

lymphoid malignancies; antagonism of the action of these proteins may enhance response

to therapy and overcome chemoresistance, and thus, these proteins of the apoptotic

pathway are compelling targets for anticancer therapy [1].

Venetoclax has been studied in multiple clinical trials and has demonstrated efficacy in

patients with hematologic malignancies as both a single agent and combination therapy

[2-7]. The pharmacokinetics of venetoclax has been characterized in several studies [2,

8–11]. Venetoclax plasma concentration peaked around 6 to 8 hours after a single dose

and the terminal phase elimination half-life (t1/2) was approximately 19 hours in subjects

with chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma (SLL). At

steady state, venetoclax area under the plasma concentration time curve (AUC) increased

proportionally over the dose range of 150 to 800 mg/day [2]. Food increased venetoclax

exposure by 3-5 fold [9, 10]. Following a single oral dose of 200 mg (100 Ci) of

[14C]venetoclax to four healthy volunteers, recovery of total radioactive dose was 100%

(± 5%), with faeces being the major route of elimination of the administered dose,

whereas urinary excretion was minimal (<0.1%) [11].

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The chemical structure of venetoclax and M27 has been previously reported [11,12].

Nonclinical studies indicated that venetoclax and its major metabolite (M27), formed by

oxidation, are metabolized primarily by CYP3A [11]. Ketoconazole is the prototypical

azole class antifungal agent. Ketoconazole was selected in this study because it is a

potent inhibitor of CYP3A4 and recommended by the Food and Drug Administration as a

probe drug for investigating the effect of inhibition on the pharmacokinetics of CYP3A

substrates [13]. Coadministration of ketoconazole may result in increased plasma

concentrations of drugs primarily metabolized by cytochrome P450 (CYP) 3A4, which in

turn could increase or prolong their therapeutic and adverse effects. Additionally, other

frequently used azole antifungal agents, such as posaconazole and fluconazole, used to

treat fungal infections in patients with cancer have been shown to inhibit CYP3A

enzymes. In vitro, venetoclax is also shown to be a substrate of P-gp and BCRP, which

are inhibited by ketoconazole [14]. Therefore, the current study was conducted to assess

the effect of ketoconazole on the pharmacokinetics of venetoclax and guide dosing

recommendations in patients requiring concomitant use of CYP3A inhibitors with

venetoclax.

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Methods

Patients

Adult men and women 18 years of age and older with relapsed or refractory (R/R)

Non-Hodgkin lymphoma (NHL) with an Eastern Cooperative Oncology Group (ECOG)

performance score of between 0 and 2 were eligible to enroll in the study. Patients were

required to have adequate bone marrow, coagulation, renal, and hepatic function. Patients

must not have used any of the following drugs/agents before study drug administration

and during the study until completion of Study Day 12: biologic agents used for

antineoplastic intent within 8 weeks; anticancer therapy or investigational drug therapy

within 14 days; corticosteroid therapy for antineoplastic intent, CYP3A inhibitors such as

ketoconazole, fluconazole, and clarithromycin, CYP3A inducers such as carbamazepine,

phenytoin, rifampin and St. John's wort, or warfarin within 7 days; or grapefruit,

grapefruit products, Seville oranges, or starfruit within 3 days.

Study Design

This was a Phase 1, open-label, single sequence study (NCT01969669) conducted at The

Cancer Center at Hackensack University Medical Center (Hackensack, NJ), Darthmouth-

Hitchcock Medical Center (Lebanon, NH), and The University of Arizona Cancer Center

(Tucson, AZ). The study was conducted in accordance with Good Clinical Practice

guidelines and ethical principles that have their origin in the Declaration of Helsinki. The

study protocol was approved by the institutional review boards (Western Institutional

Review Board, Olympia, WA; Dartmouth College Committee for the Protection of

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Human Subjects, Hanover, NH) and written informed consent was obtained from each

patient before any study-related procedures were performed.

Each patient received a single 50 mg tablet of venetoclax (AbbVie Inc., North Chicago,

IL) on Days 1 and 8. On Days 5–11, each patient received two tables of 200 mg

ketoconazole (Mylan Pharmaceuticals, Canonsberg, PA) (Figure 1). All tablets were

swallowed in the morning with 240 mL of water, within 30 minutes after completion of a

standardised low-fat breakfast.

Blood Sample Collection and Bioanalytical Methods

Blood samples for venetoclax and M27 assay were collected in 3 mL

K2EDTA-containing plastic tubes by venipuncture prior to dosing (0 hour) and at 2, 4, 6,

8, 10, 12, 24, 48, 72, and 96 hours after dosing on Day 1 and Day 8. Plasma

concentrations of venetoclax and M27 metabolite were determined using liquid

chromatography with tandem mass spectrometric detection [12]. The lower limits of

quantitation for the venetoclax and M27 assays were 2.05 and 2.04 ng/mL, respectively.

The precision values for the quality control samples of venetoclax and M27 were ≤ 12.2%

and ≤ 11.6%, respectively.

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Pharmacokinetic Analysis

The pharmacokinetic parameters of venetoclax and M27 metabolite on Day 1 and Day 8

were estimated using noncompartmental methods in SAS v9.2. Pharmacokinetic

parameters estimated included: the maximum observed concentration (Cmax), the time to

maximum concentration (Tmax), the apparent terminal phase elimination rate constant (β),

the terminal phase elimination half-life (t1/2), the AUC from time 0 to time of the last

measurable concentration (AUCt) and extrapolated to infinite time (AUC∞).

Safety and Tolerability Assessments

Treatment-emergent adverse events were defined as adverse events with onset after the

first dose of venetoclax through the end of the study. The number and percentage of

subjects having treatment-emergent adverse events were summarized with a breakdown

by the following three regimens: before ketoconazole administration (venetoclax alone,

Days 1 through 4), ketoconazole alone (Days 5 to 7), and venetoclax and ketoconazole

coadministration (Day 8 to the end of the study). Adverse event severity was classified

according to National Cancer Institute (NCI) Common Toxicity Criteria for Adverse

Events (CTCAE) Version 4.0 toxicity grade. Serious adverse events and events leading

to discontinuation of treatment were summarized. Laboratory test results and vital signs

values were evaluated for possible clinical significance using predefined criteria.

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Statistical Analysis

To assess the effect of ketoconazole on venetoclax and M27 pharmacokinetics, an

analysis of variance (ANOVA) was performed for Tmax, β, and the natural logarithms of

Cmax, AUCt and AUC∞ using PROC GLM in SAS v9.2. The model included a fixed

effect for Day (venetoclax alone – Day 1 and venetoclax in combination with steady-state

dose ketoconazole – Day 8). Patients were treated as a random effect in the model.

Within the ANOVA modeling framework, the null hypothesis of no difference between

venetoclax with ketoconazole (Day 8) relative to venetoclax alone (Day 1) was tested

with a significance level of 0.05.

The relative exposure of venetoclax with ketoconazole (Day 8) compared to venetoclax

alone (Day 1) was assessed using 90% confidence intervals for difference of the least

square means obtained from ANOVA of the natural logarithms of Cmax, AUCt, and AUC∞

on Day 1 and Day 8. The 90% confidence intervals were obtained for those ratio

estimates by taking the antilogarithm of the upper and lower limits of confidence intervals

for the difference of least square means of the logarithmic scale obtained within the

framework of the ANOVA model.

The power calculations assumed the error term variance of 0.1724 for the natural

logarithm of dose-normalized Cmax. Complete data from 10 subjects would provide at

least 80% power to detect an 80% increase (or 45% decrease) in the central value of C max

between the two regimens (venetoclax alone versus venetoclax in combination with

ketoconazole).

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Results

Patients and Baseline Demographic Characteristics

Twelve patients were enrolled in the study. All 12 patients completed the study. Their

mean (standard deviation [SD]) weight was 83.3 (18.5) kg and the median age was

71.5 years (range: 37 – 82) (Table 1). One patient was excluded from the statistical

analysis of pharmacokinetic parameters because the protocol-specified dose of

ketoconazole 400 mg was not taken on Day 6 through Day 8; the subject took

ketoconazole 200 mg on these days. Following dosing on Day 8, two pharmacokinetic

samples in the terminal elimination phase (48 and 96 hour) were not collected for one

subject. AUC∞ and t1/2 were not calculated for this subject on Day 8, as valid estimates

of β could not be determined.

Effect of Ketoconazole on Venetoclax and M27 Pharmacokinetics

The mean (+ SD) plasma concentration-time profiles for venetoclax and M27, following

administration of 50 mg venetoclax alone on Study Day 1 and coadministration with

ketoconazole on Study Day 8, are presented in Figure 2. Pharmacokinetic parameters of

venetoclax and M27, with and without ketoconazole, are presented in Table 2. After a

50 mg oral dose, the median time to reach peak plasma concentrations of venetoclax was

8 hours on Study Day 1 with a mean t1/2 of 19.1 hours.

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When venetoclax was coadministered with ketoconazole, the venetoclax median Tmax did

not change but the venetoclax Cmax, AUCt, AUC∞, and t1/2 were significantly increased

(P < 0.05). Ketoconazole increased venetoclax Cmax and AUC∞ in all subjects (Figure 3)

with a mean increase of 2.3- and 6.4-fold, respectively, compared to administration of

venetoclax alone (Table 3). While the mean increase in AUC was 6.4-fold, the variability

was high (range: 2- to 12-fold increase). Two subjects reported receiving

acid-suppressing agents during the study. No change in point estimates for venetoclax

Cmax and AUC∞ were noted in the analysis conducted excluding data from these

two subjects. One subject reported taking a protocol exclusionary medication, diltiazem,

a moderate CYP3A inhibitor, before and throughout the study. Analyses conducted

excluding this subject showed no change in point estimate for venetoclax Cmax (2.3-fold)

and a slight increase in AUC∞ (7.2-fold vs. 6.4-fold) following coadministration with

ketoconazole. Interestingly, the one subject who was excluded from statistical analysis

for reporting to take incorrect ketoconazole dose of 200 mg on days 6 through 8 showed a

2.3-fold increase in Cmax and 3.5-fold increase in AUC, suggesting the interaction was

perhaps not maximal at 200mg ketoconazole daily; although, given the large variability in

AUC increases observed in this study, this may have merely been due to interpatient

variability.

In contrast to venetoclax, M27 metabolite Tmax was delayed and both Cmax and AUCt

decreased in most subjects with a mean decrease in Cmax and AUCt by approximately

50% and 30%, respectively, after coadministration of venetoclax with ketoconazole

(Table 3).

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Safety and Tolerability

Five patients (41.7%) reported adverse events when treated with venetoclax alone,

2 (16.7%) patients reported adverse events when treated with ketoconazole alone, and

8 (66.7%) patients reported adverse events when treated with the combination of

venetoclax and ketoconazole. The majority of adverse events reported were mild or

moderate in severity (grade 1 or grade 2). One subject experienced a Grade 3 adverse

event of hypokalaemia on the day of treatment with venetoclax alone. This adverse event

ended after 2 days and was not considered by the investigator or sponsor to be related to

venetoclax treatment. Grade 3 events of thrombocytopenia and ureteric obstruction were

reported when venetoclax was coadministered with ketoconazole. Thrombocytopenia

was considered by the investigator as possibly related to both venetoclax and

ketoconazole treatment and was ongoing at the end of the study; the ureteric obstruction

(the only serious adverse event reported in this study) which occurred on Day 11 was

considered by the investigator to be unrelated to either study drug. No deaths were

reported and there were no interruptions, reductions, or discontinuations of venetoclax or

ketoconazole due to adverse events. Four adverse events in clinical laboratory

investigations were reported (grade 2 hyperphosphatemia, grade 1 serum creatinine

increase, grade 2 hyperkalemia, grade 2 hypocalcemia); all were nonserious and resolved

with no action taken with regard to study drug administration. No clinically meaningful

abnormalities in vital signs, electrocardiogram parameters, or other laboratory values

were observed.

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Discussion

This is the first clinical pharmacokinetic study to determine the potential effect of any

CYP3A inhibitor on the pharmacokinetics of venetoclax in patients with hematological

malignancies. In this study, treatment with oral ketoconazole increased venetoclax mean

Cmax and AUC∞ by 2.3– and 6.4–fold, respectively, compared to venetoclax alone. An

increase in venetoclax AUC∞ of 6.4–fold combined with a > 2–fold increase in its t1/2

strongly suggests the key role of CYP3A4 in venetoclax elimination in patients.

Inhibition of p-glycoprotein (P-gp) and breast cancer resistance protein (BCRP) may have

also contributed to the increase in venetoclax exposures via an increase in absorption as

ketoconazole has inhibitory effects on P-gp and BCRP [14]. It must be noted that while a

dose of 50 mg was used in this study, higher doses (e.g.,: 400 mg) are used

therapeutically and the magnitude of the interaction at higher doses might be different.

Although the range of body weight of patients enrolled in the study was wide (50.8-119

kg), it must be noted that no relationship between body weight and AUC ∞ was observed

(Figure 4). Additionally, majority of the subjects were males and white. In an earlier

study, the covariates weight, sex, and race did not affect venetoclax clearance [10].

Ketoconazole effects on venetoclax pharmacokinetics were less profound in magnitude

when compared to the effects observed on midazolam, a sensitive and often used CYP3A

probe substrate. Stoch et al reported an increase of 5.4- and 14.0-fold in Cmax and AUC∞

of midazolam in a healthy volunteer study in which ketoconazole 400 mg once daily was

administered for 5 days and a 2 mg midazolam dose was coadministered with

ketoconazole on Day 5 [15].

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Plasma concentrations of ketoconazole were not measured to confirm compliance with

ketoconazole therapy. An AUC increase of > 5-fold in the presence of ketoconazole

indicates that venetoclax is a sensitive CYP3A substrate. The exposure-efficacy analyses

using data from CLL subjects indicated that the rate of objective response is similar, with

0.5- to 2.0-fold change in exposure from that typically achieved at the 400 mg QD dosage

regimen [16]. At a venetoclax dose of 1200 mg QD, where venetoclax exposures are

approximately 2.5-fold higher than those achieved at 400 mg QD, the maximum tolerated

dose of venetoclax was not reached [17,18,19]. On the other hand, venetoclax therapy in

CLL patients starts according to a weekly ramp-up dosing schedule from 20 mg to the

recommended dose of 400 mg over a period of 5 weeks to minimize the risk for tumor

lysis syndrome. Therefore, based on the results from this study and the exposure–

efficacy and safety venetoclax profile, coadministration of venetoclax with moderate and

strong inhibitors or inducers of CYP3A should be avoided during the ramp-up phase in

CLL patients. For patients who have completed the ramp-up phase, a modification of

venetoclax dose for use with strong inhibitors or inducers of CYP3A/P-gp is

recommended.

M27 mean Cmax and AUCt decreased by approximately 50% and 30%, respectively, after

coadministration of venetoclax with ketoconazole. A decrease in Cmax of M27 can be

explained by its decreased rate of formation from venetoclax mediated by CYP3A

inhibition. However, a decrease in AUCt was not expected given that M27 is also a

CYP3A substrate and its metabolic clearance was reduced in the presence of

ketoconazole. The decrease in AUCt is an artifact of the shorter pharmacokinetic

sampling duration. M27 Tmax was significantly delayed (median = 48 hours), only two

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PK samples were collected beyond Cmax (at 72 and 96 hours) and the half-life of M27 was

significantly prolonged in the presence of ketoconazole. Taken together, this resulted in

inability to accurately calculate M27 AUC∞ and t1/2 on Day 8 for 8 subjects, as valid

estimates of β could not be determined due to the lack of 3 concentration time data points

after Tmax. In 4 subjects where AUC∞ estimates could be calculated, the % extrapolated

AUC was very high (> 50%), further emphasizing the limitation of a shorter PK sampling

duration. It is worth noting that the M27 metabolite was not identified at the time of

study design and conduct and hence the PK sampling scheme was based solely on the

expected effect on venetoclax pharmacokinetics. If M27 concentrations were measured

long enough, both M27 AUCt and AUC∞ estimates would have been higher as can be

inferred from Figure 2 showing relatively flat M27 concentrations in the presence of

ketoconazole beyond 24 hours. Overall, the results observed are consistent with those

expected from CYP3A inhibition of venetoclax and M27 metabolism and M27 formation

from venetoclax.

The pharmacokinetics of navitoclax, a dual inhibitor of BCL-2 and BCL-XL, were not

significantly affected by ketococonazole [20] suggesting that, unlike venetoclax, CYP3A

does not play a major role in the elimination of navitoclax. Thrombocytopenia caused by

BCL-XL inhibition has been the primary dose-limiting toxicity in the clinical

development of navitoclax. Venetoclax. a selective BCL-2 inhibitor, has an improved

safety profile than dual BCL-2/BCL-XL inhibitors by avoiding dose-limiting

thrombocytopenia. In this study, grade 3 thrombocytopenia was reported only in one

subject (8.3 %), a frequency similar to that reported previously in a Phase 1 venetoclax

monotherapy study in R/R NHL patients [17]. Venetoclax exposures in this subject were

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within the range of exposures observed in other subjects who did not develop

thrombocytopenia. Overall, coadministration of venetoclax with and without

ketoconazole was well tolerated in this Phase 1 study in 12 patients with relapsed or

refractory NHL with no other serious (grade 3, 4, or 5) adverse events attributed to study

drugs.

Conclusions

Coadministration of venetoclax with multiple doses of ketoconazole resulted in a

significant increase of venetoclax exposures strongly suggesting that CYP3A plays a

major role in elimination of venetoclax in patients. Due to the potential risk for the

occurrence of tumor lysis syndrome with elevated venetoclax exposures in patients with

certain types of cancer, such as CLL, these results suggest the need to avoid concomitant

use with strong and moderate inhibitors or inducers of CYP3A during the venetoclax

ramp-up phase. For patients who have completed the ramp-up phase and are on a steady

daily dose, a modification of venetoclax dose for use with strong inhibitors or inducers of

CYP3A/P-gp is recommended.

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 Acknowledgements

We thank the patients (and their families) who participated in the study, the clinical site

research personnel, and AbbVie personnel for their contributions to various aspects of the

study. In addition, we thank Ms. Amy Rohrlack of AbbVie for medical writing support.

All authors contributed to the study concept and design, analysis and interpretation of

data, and development and approval of the manuscript. AbbVie and Genentech/Roche

provided financial support for the study and participated in the design, study conduct,

analysis and interpretation of data as well as the writing, review and approval of the

manuscript. Venetoclax is being developed in a collaboration between AbbVie and

Genentech/Roche.

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Figure 1. Study Design

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Figure 2. Plasma Venetoclax and M27 Metabolite Concentration (Mean + SD) vs.
Time Profiles Following Administration of 50 mg Venetoclax Alone on Day 1 and
With 400 mg Ketoconazole on Day 8 (N = 11)

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Figure 3. Individual Venetoclax Cmax and AUC∞ Values After Administration of 50
mg Venetoclax Alone on Day 1 and After Coadministration with 400 mg
Ketoconazole on Day 8 (N = 11). *Red line denotes the subject who experienced
thrombocytopenia and also took diltiazem, a moderate CYP3A inhibitor, throughout the
study.

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Figure 4. Relationship Between Body Weight and AUC∞ on Day 1

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Table 1. Demographic and Baseline Characteristics of the Subjects Enrolled in
the Study

Characteristic N = 12
Gender, n (%) Female 1 (8.3)
Male 11 (91.7)
Age, yrs Mean (SD) 66.3 (13.17)
Median 71.5
Range 37 – 82
Age, n (%) ≤ 65 yrs 5 (41.7)
66 – 75 yrs 3 (25.0)
> 75 yrs 4 (33.3)
Weight, kg Mean (SD) 83.3 (18.5)
Median 81.5
Range 50.8 – 119.0
Height, cm Mean (SD) 172.7 (9.88)
Median 173.6
Range 148.2 – 183.0
Tobacco use Current user 2 (16.7)
Former user 5 (41.7)
Never used 5 (41.7)
Ethanol use Current user 7 (58.3)
Former user 3 (25.0)
Never used 2 (16.7)

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Table 2. Mean ± SD (Range) Pharmacokinetic Parameters of Venetoclax and
M27 Metabolite
a
Regimens
Reference: Venetoclax Alone Test: Venetoclax with Ketoconazole
Pharmacokinetic Day 1 Day 8
Parameters (units) (N = 11) (N = 11)
Venetoclax
b
Tmax (h) 8 (4, 12) 8 (0, 12)
c
Cmax (µg/mL) 0.212 ± 0.083 (0.126, 0.356) 0.488 ± 0.173 (0.278, 0.830)
c
AUCt (µg•h/mL) 4.32 ± 2.21 (1.69, 8.35) 19.9 ± 10.4 (9.21, 42.2)
c,d
AUC∞ (µg•h/mL) 4.52 ± 2.38 (1.73, 8.95) 35.6 ± 33.5 (10.9, 113)
e c,d
t1/2 (h) 21.2 ± 5.77 (8.26, 31.7) 66.9 ± 84.9 (18.5, 306)
M27 Metabolite
b c
Tmax (h) 24 (11.5, 24) 48 (4, 72)
c
Cmax (µg/mL) 0.020 ± 0.010 (0.009, 0.042) 0.010 ± 0.005 (0.006, 0.020)
AUCt (µg•h/mL) 1.08 ± 0.58 (0.544, 2.50) 0.77 ± 0.39c (0.348, 1.55)
f
AUC∞ (µg•h/mL) 1.48 ± 0.84 (0.643, 3.55) 2.45 ± 1.11 (1.48, 3.43)
e c,f
t1/2 (h) 43.0 ± 14.0 (21.8, 74.8) 194 ± 89.7 (98.5, 299)
a. Reference regimen (venetoclax alone) venetoclax 50 mg administered under nonfasting conditions as a single dose on
Day 1.
Test regimen (venetoclax with ketoconazole) ketoconazole 400 mg QD administered under nonfasting conditions on
Days 5 through 11; on Day 8, venetoclax 50 mg administered as a single dose under nonfasting conditions.
b. Tmax reported as median (range).
c. Statistically significant from reference regimen.
d. N = 10; estimates of AUC∞ and t1/2 could not be calculated for one patient.
e. Evaluations of t1/2 were based on statistical tests for β.
f. N = 4; estimates of AUC∞ and t1/2 could not be calculated in seven patients in this regimen.

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Table 3. Point Estimates and 90% Confidence Intervals of Venetoclax and M27
Metabolite Pharmacokinetic Parameters

Regimens
a
Pharmacokinetic Central Value Point 90% Confidence
Test vs. Reference Parameter (units) Test Reference Estimate Interval
Venetoclax
Venetoclax w/ Cmax (µg/mL) 0.461 0.198 2.323 1.996 – 2.702
Ketoconazole (Day 8) AUCt (µg•h/mL) 17.887 3.803 4.703 3.549 – 6.233
vs. Venetoclax Alone b
(Day 1) AUC∞ (µg•h/mL) 25.366 3.961 6.403 4.472 – 9.168

M27 Metabolite
Venetoclax w/ Cmax (µg/mL) 0.009 0.018 0.499 0.419 – 0.595
Ketoconazole (Day 8) AUCt (µg•h/mL) 0.694 0.968 0.717 0.634 – 0.812
vs. Venetoclax Alone c
(Day 1) AUC∞ (µg•h/mL) 2.356 1.308 1.801 0.961 – 3.376

a. Reference regimen (venetoclax alone) venetoclax 50 mg administered under nonfasting conditions as a single dose on
Day 1.
Test regimen (venetoclax with ketoconazole) ketoconazole 400 mg QD administered under nonfasting conditions on
Days 5 through 11; on Day 8, venetoclax 50 mg administered as a single dose under non-fasting conditions.
b. N = 10.
c. N = 4.

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